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AXL-TBK1 driven AKT3 activation promotes metastasis

Emily N Arner1,2, Dina Alzhanova2, Jill M Westcott2

  • 1Cancer Biology Graduate Program, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Science Signaling
|December 17, 2024
PubMed

Insights

AXL activation triggers AKT3 and Snail signaling, promoting cancer EMT and metastasis. Inhibiting AKT3 may offer a new therapy for aggressive cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Signaling Pathways

Background:

  • The receptor tyrosine kinase AXL drives tumor progression, metastasis, and therapy resistance.
  • AXL induces epithelial-mesenchymal transition (EMT), a key process in cancer spread.

Purpose of the Study:

  • To elucidate the downstream signaling pathway activated by AXL that promotes EMT.
  • To investigate the role of AKT3 in AXL-mediated EMT and cancer progression.

Main Methods:

  • Investigated AXL-induced phosphorylation of TANK-binding kinase 1 (TBK1).
  • Assessed the interaction and phosphorylation of AKT3 by TBK1, dependent on mTORC1.
  • Examined AKT3's role in Snail nuclear accumulation and EMT marker expression.
  • Analyzed AKT3 and Snail co-localization in human pancreatic ductal adenocarcinoma tissues.
  • Evaluated the impact of AKT3 deficiency on metastasis in mouse models.

Main Results:

  • AXL activation led to TBK1 phosphorylation and downstream activation of AKT3 and Snail.
  • TBK1 directly bound and phosphorylated AKT3, a process dependent on the mTORC1 complex.
  • Activated AKT3 promoted Snail nuclear accumulation, enhancing EMT.
  • Nuclear AKT3 and Snail co-localized in human pancreatic tumors and correlated with poor outcomes.
  • AKT3-deficient mouse pancreatic cancer cells exhibited reduced metastatic spread.

Conclusions:

  • The AXL-TBK1-AKT3-Snail axis is a critical pathway for EMT induction and cancer progression.
  • Nuclear AKT3 is a potential biomarker for aggressive pancreatic cancer.
  • Targeting AKT3 presents a promising therapeutic strategy for inhibiting EMT in aggressive cancers.

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